Oxindoles, with C-3 functionalisation resulting in quaternary centre at C-3 position constitute a common structural backbone for several drug candidates and bioactive natural products. In particular, 3-substituted-3-hydroxyoxindole is an emerging scaffold for several pharmacologically active alkaloids such as dioxibrassinine, CPC-1, Donaxaridine, Maremycin A and B, Horsfiline, spirobrassinin in addition to several others contain 3-hydroxyoxindole moiety.
For detailed discussion of biological significance of 3-substituted-3-hydroxyoxindoles refer “3-Substituted-3-hydroxy-2-oxindole, an Emerging New Scaffold for Drug Discovery with Potential Anti-Cancer and other Biological Activities” reported by Peddibhotla in Curr. Bioact. Compd. 2009, 5, 20. In this review paper synthesis, isolation, bio-activity and medicinal chemistry aspects of these 3-substituted-3-hydroxyoxindoles scaffolds are described.
It is important to note that, prior to 1935, 3-hydroxy-3-nitromethylindolin-2-ones (which is a Henry Adduct) had never been successfully prepared. In 1936 the synthesis of 3-hydroxy-3-nitromethylindolin-2-ones was achieved for the first time [Lindwall J. Am. Chem. Soc. 58, 1236 (1936)]. The inherent disadvantages of the process adopted by Lindwall are the usage of additives and expensive solvents with low yields of the desired products in long reaction hours.
Reference may be made to the publication, Tetrahedron 2008, 64, 5915 wherein synthesis of 3-hydroxy-3-nitromethylindolin-2-ones was achieved by electro-catalytic methods. The inherent disadvantages of the disclosed process are the usage of expensive solvents with low yields of the desired products.
Reference may be made to the publication, Tetrahedron Letters 2011, 52, 5862 wherein synthesis of 3-hydroxy-3-nitromethylindolin-2-ones was attained using DABCO as catalyst. The inherent disadvantage of the disclosed process is the usage of expensive DABCO ligand and difficulty in the recovery of pure product as under strong basic conditions there is every possibility of rearrangement of the product.
Other related prior arts on oxindoles are:
US 2004/0014986 A1January 2004Hendel et alU.S. Pat. No. 7,595,338 B2September 2009Wilk et alU.S. Pat. No. 5,047,554 B2September 1991Ehrgott et alUS 2011/0105804 A1May 2011Major et al
Despite the continued interest being shown, there is a continued need to develop further derivatives of 3-hydroxy-3-nitromethylindolin-2-ones and also to develop efficient and less expensive synthetic route for preparing 3-hydroxy-3-nitromethylindolin-2-one and its further derivatives which can be used as value added synthetic precursors, wherein such value added synthetic precursors can act as starting materials for several useful drug candidates.